Intranasal immunization can induce not only systemic, but also mucosal immunity, is easy to administer, and is suitable for mass immunization. These advantages of nasal immunization are particularly relevant to influenza virus which affects respiratory mucosal surfaces and constantly poses the danger of a pandemic. Inactivated influenza antigens however, are poor immunogens by themselves when delivered via the intranasal route. Our objective is to develop an inactivated whole virion influenza nasal powder vaccine incorporating a novel in-situ gelling nasal delivery system (GelVac(tm)). Vaccines containing whole virion antigens are more immunogenic and faster to manufacture. Being inactivated, this vaccine does not have the shortcomings of a live vaccine. Furthermore, powder formulations have critical advantages as a biodefense tool, including better stability and cold-chain-free distribution. Thus, the advantages of inactivated whole virion antigen, powder formulation, and nasal delivery with the GelVac system are combined together in this one vaccine. The GelVac system utilizes an enabling excipient and is an integral part of this vaccine. It is based on the GelSite(tm) polymer, a unique acidic high molecular weight plant polysaccharide currently manufactured under cGMP. It confers two critical properties to the vaccine: mucoadhesive and in-situ gelling - changing from a powder to a gel upon contact with nasal fluid and thereby providing a sustained antigen release. Our preliminary studies have shown that intranasal delivery with GelVac powder formulations significantly increases serum IgG and lung IgA responses against inactivated split subvirion influenza antigen. The proposed studies include 1) formulation development, 2) immunogenicity and protection, and 3) animal toxicity studies. Two vaccine candidates, a monovalent H5 subtype and a trivalent consisting of the three virus strains in current inactivated influenza vaccines, will be developed. Completion of these preclinical studies will form the basis for an IND submission.